New synthesis for the preparation of 3-hydroxy-N-alkylisomorphinans

ABSTRACT

3-Hydroxy-N-alkylisomorphinans are compounds known to possess valuable properties as narcotic analgetics and/or antagonists. The commercial use of these compounds has not been practical due to the high cost of making these compounds. A new synthesis has been found which provides the compounds in commercial yields via a total synthesis.

United States Patent Monkovic et al.

Oct. 7, 1975 NEW SYNTHESlS FOR THE PREPARATION OF 3-HYDROXY-N-ALKYLISOMORPHINANS lnventors: Iva Monkovic; Henry Wong, both of Candiac, Canada Assignee: Bristol-Myers Company, New York,

Filed: Nov. 7, 1973 Appl. No.: 413,463

Related U.S. Application Data Division of Ser. No. 229,20l, Fel:v 24, 1972, Pat. No. 3,803,]50

U.S. Cl. 5. 260/285; 260/283 SY; 260/558 P lnt. Cl. C07D 221/38 Field of Search 260/285 References Cited UNITED STATES PATENTS l0/l956 Gates 260/285 OTHER PUBLICATIONS Bien et al., Chemical Abstracts, Vol. 58, lOl65 f (1963).

Primary Examiner-Donald G. Daus Assistant Examiner-Diana G. Rivers Attorney, Agent, or FirmRobert E. Havranek 4 Claims, No Drawings NEW SYNTHESIS FOR THE PREPARATION OF 3-HYDROXY-N-ALKYLISOMORPHINANS CROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisional application of copending application Ser. No. 229.201. filed Feb. 24, 1972 now US. Pat. No. 3,803,l5().

BACKGROUND OF THE INVENTION -CH2 -Y in which Y is cyclobutyl or cyclopropyl as possessing analgetic and/or narcotic antagonist activity.

B. M. Gates and T. Montzka [1. Med. Chem., 7. I27 (1964)] report the synthesis of morphinans and isomorphinans of the formula in which Y is cyclopropylmethyl, cyclobutylmethyl, l-phenylcyclopropylmethyl, methyl, cyano, H, etc. and R is methyl or H.

C. M. Gates and W. Webb. [1. Am. Chem. Soc. 80, H86 1958)] also report similar compounds the most pertinent of which appears to be that having the formula N- CH SUMMARY OF THE INVENTION lsomorphinan compounds having the formula XII wherein R is (lowerJalkyl,

(CH ),,C. I-I;, in which R is H or CH and n is an integer of l to 3; or a pharmaceutically acceptable acid addition salt thereof are prepared by the consecutive steps of A. uc'yluring the compound having the formula in which R is (lower)alkyl to produce a compound having the formula VII in which R is as above, R is (lower)alkyL (CH )H l$ 5v in which R is H or CH;, and n is an integer of I) to 2;

B. hydrating compound VII by treatment with boron trihydride and then with hydrogen peroxide in the presence of base to produce the compound having the formula VIII in which R and R are as above;

C. eslerijjving compound VIII with methylsulfonyl chloride to produce the compound having the formula H 2 I H ll 1 R 0 N-C-R in which R and R are as above;

D. cyclizing compound [X by treatment with sodium hydride to produce a compound having the formula in which R" and R are as above.

E. reducing compound X wherein R is (lower)alkyl and R is -C (lower)alkyl,

or (CH ),,-C H;,, in which R is H or (lowerJalkyl and n is an integer of l to 2 with lithium aluminum hydride to produce the compound having the formula XIp in which R is (lower)alkyl and R is C C (lowerJalkyl.

in which R" is H or CH;, and n is an integer of l to 3; and

F. clearing the ether function of compound Xlp to produce compound Xllp wherein R is H.

Compounds having the formula patent, are derived from opium alkaloids; expensive M starting materials. In addition. the yields are low and thereby uneconomical.

4 available starting material Drug abuse by thrill-seeking youth or by people looking for an escape from the realities ofevery day life ha! become more and more common place in our present society. One class of widely abused drugs are the narcotic analgetics such as codeine, morphine, meperidine. etc. It is because of the high addictive potentia of these agents that much time and money are being ex pended by the pharmaceutical industry and by governments to try and discover and develop new non addicting analgetics and/or narcotic antagonists. The compounds of formula Xll appear to possess some oi these desirable properties.

It was therefore an object of the present invention to discover a new and economical method of preparing these compounds.

It was a further object to develop a method employing starting materials that were not opium alkaloids or derivatives thereof.

The objectives of the present invention have been achieved by the provision of the process for the total synthesis of compounds having the formula XII in which R is H or (lower)alkyl and R is selected from the group comprising (lower)alkyl,

in which R is H or CH and n is l to 3; from the readily 7-methoxy-3,4-dihydro- 1 [2H ]-naphthalen0nc.

The compounds of the instant invention have the basic morphinan nucleus numbered and represented by the following plane formula Although there are three asymetric carbons (asterisks) in the morphinan molecule, only two diastereoisomeric (racemic) forms are possible. because the iminoethano system. attached to position 9 and 13. is geometrically constrained to a cis-( 1.3-diaxial )-fusion. These racemates can therefore differ only at the junction of rings B and Cin other words. in the configure tion of carbon 14. The only variable will be the cis and trans relationship between the 5 l3) and 8 l4) bonds [Analgetics, Ed. George de Stevens, Academic Press, New York, p. l3? (1965)].

The compounds of the present invention have the 5 l 3) and 8 ]4) bonds trans to each other and are commonly designated as isomorphinans. For the purpose of this application, the use of a graphic representation of an isomorphinan is meant to include the dl racemic mixture and the resolved d and l. isomers thereof.

The isomorphinan compounds of the present invention can each exist as two optical isomers, the levorotatory and dextrorotatory isomers. The optical isomers can be graphically illustrated as:

ISOMORPHINANS The optical isomers can be separated and isolated by fractional crystallization of the diastcreoisomeric salts formed, for instance, with d or l-tartaric acid or D-(+)-0z-bromocamphorsulfonic acid.

For the purpose of this disclosure, the term (lower- )alkyl is defined as an alkyl radical containing l to 10 carbon atoms in straight or branched chains. The terms lower)alkynyl and (lower)alkenyl" are hydrocarbons of 2l() carbons with 1 triple bond and 2-10 carbons with I double bond respectively. (Lower)alkanol is a straight or branched chain alcohol of l to 10 carbon atoms.

For the purpose of this disclosure, the term acid addition salt is defined to include all those inorganic and organic acid salts of the compounds of the instant invention, which salts are commonly used to produce nontoxic salts of medicinal agents containing amine functions. Illustrative examples would be those salts formed by mixing the compounds of formula I with hydrochloric, sulfuric, nitric, phosphoric, phosphorous, hydrobromic, maleic, malic, ascorbic, citric or tartaric acid, and the like.

The compounds of the instant invention are prepared by a total synthesis comprising up to ID steps. Surprisingly, the synthesis is efficient and appears commercially feasible. The process is outlined in Charts 1, I] and Ill.

CHART I C1130 Step A E ct-I 0 Ia 0 He. 0

she? a CH 0 Step c en 0:

3 H0 3 HQ 1118. IVa. 2

9 s N H i H2 nc-Q 03 0 Example 1 c11 0 Va a VIIa .0 mesyl CHART II CH O VIIIb and CHART III I N-CHz -CH=CH2 EH 0 Examgle 12 E Cl-I3 XId XIIIa CHART 3 -Continued Example 14A XIf A Preferred embodiment of the W invention is with at least one mole of an acylating agent having the the process of preparing compounds having the for f l mula l W 45 R c x or R '(-0(R' in which X is OH, Cl, Br or I, R is (lower)alkyl, -.z) H m 6 mp or 1 H3 wherein R is C -C1" l l yL z)|| u in which R" is H or CH;, and n is an integer of l or 2, 6 55 or a functional equivalent thereof for the acylation of 6 R a primary amine, in an inert organic solvent, in the *CH-fq- R ('H@ or fl. resence of at least one mole ofa tertiary amine to pro- CH duce the compound having the formula in which R is H or CH;; and n is an integer of l to 3; 60

which process Comprises the consecutive steps of 0 A, ucyluling l mole of the compound having the for- 2 H 4 R 0 N-C-R multi s5 VIIp R20 in which R and R are as above;

V B. treating 1 mole of compound Vllp with at least two mole of boron trihydride, in an anhydrous organic solvent, and subsequently with at least one mole of hydrogen peroxide and water in the presence of an alkali metal hydroxide to produce the compound having the formula vnl in which R and R are as above;

C. estelijiving 1 mole of compound Vlllp with at least one mole of a (lower)alkyl, benzene or toluene sulfo nyl, halide; or its equivalent, in the presence of at least one mole ofa tertiary amine in an inert organic solvent, to produce the compound having the formula in which R and R are as above;

D. cyclizing 1 mole of compound lXp by treatment with at least one mole of sodium hydride, in an inert or ganic solvent, to produce the compound having the formula in which R and R are as above;

E. reducing one mole of compound X with an excess of lithium aluminum hydride in an inert solvent with the aid of heat to produce the compound having the formula XIp bl J

lected from the group comprising methylene chloride, benzene, xylene, ether, dichloroethane or chloroform, in the presence of at least one mole of a tertiary amine selected from the group comprising triethylamine, trimethylamine, pyridine, N-methylpiperidine or N- methylpyrrolidine, to produce compound Vllp', in step B one mole of compound Vllp is treated with about L5 to about 4 moles of boron trihydride, in an anhydrous organic solvent selected from the group comprising dry tetrahydrofuran, benzene, dioxane, diethyl ether, di propylethyl or dibutyl ether, for about 2 to 24 hours, at a temperature in the range of about 0 C. to about 30 C., following which the mixture is treated with at least an equimolar quantity each of hydrogen peroxide, water and an alkali metal hydroxide with the aid of heat to produce the compound having the formula Vlllp; in step C esterifying one mole of compound Vlllp with about 1.0 to 2.0 moles of a (lower)alkyl sulfonyl Chloride, in the presence of about 1.0 to 3.0 moles ofa tertiary amine selected from the group comprising triethylamine, trimcthylamine, pyridine, N-methylpiperidine or N-methylpyrrolidine, in an organic solvent selected from the group comprising benzene, xylene, toluene, methylene chloride or dichloroethane, to produce compound lXp; in step D cyclizing one mole of compound lXp by treatment with about L0 to about 2.0 moles of sodium hydride in an organic solvent selected from the group comprising dimethylformamide, dimethylacetamide, benzene, toluene, xylene, tetrahydrofuran, dioxane, at about room temperature for a period of about 5 to about 25 hours, to produce compound Xp; in step E reducing one mole of compound Xp with about 1.0 to about 20 moles of lithium aluminum hydride in an organic solvent selected from the group comprising tetrahydrofuran, dioxane, diethyl ether, dipropyl ether or dibutyl ether, with the aid of heat, to produce compound Xlp; and in step F cleaving the ether function of 1 mole of compound Xlp by treatment with an agent selected from the group comprising hydrobromic acid, boron tribromide or pyridine hydrochloride to produce compound Xllp.

A more preferred embodiment is the process for the preparation of compound Xllp wherein in step A one mole of compound V in which R is methyl is acylated with about L0 to about 1.2 moles of acylating agent having the formula in which X is Cl, Br or I and R is (lower)alkyl, (CH ),,C Hs,

in which R is H or CH;, and n is an integer of l or 2, in methylene chloride or dichloroethane, in the presence of about I to about 2 moles of triethylaminc or pyridine to produce compound Vllp, in step B treating one mole of compound Vllp with about 2 to about 3 moles of boron trihydride in tetrahydrofuran or dioxane, and l to 2 moles each of hydrogen peroxide, water and sodium or potassium hydroxide to produce compound Vlllp; in step C esterifying one mole of compound Vlllp with about 1.1 to about 1.6 moles of methylsulfonyl chloride, in the presence of about 1.1 to about 1.6 moles of triethylamine or pyridine in benzene, toluene or xylene to produce compound IXp; in step D cyclizing one mole of compound lXp with about 1.3 to 1.7 moles of sodium hydride in dimethylformamide or dimethylacetamide to produce compound Xp; in step E reducing one mole of compound Xp with about 1.0 to about 1.5 moles of lithium aluminum hydride in anhydrous tetrahydrofuran or dioxane at about reflux temperatures to produce compound Xlp; and in step F cleaving the ether function of Xlp by treatment with about 1.5 to about 4.0 moles of boron tribromide, hydrobromic acid or pyridine hydrochloride to produce compound Xllp.

A most preferred embodiment is the process for the preparation of compound Xllp in which R is wherein in step A one mole of compound V in which R is methyl is acylated with about 1.0 to about 1.2 moles of eyclobutylcarbonyl chloride or cyclopropyl carbonyl chloride in methylene chloride, in the presence of 1.0 to 1.3 moles of triethylamine to produce compound Vllp; in step B treating one mole of compound Vllp with about 2 to 3 moles of boron trihydride in tetrahydrofuran, followed by 1.0 to 1.3 moles each of hydrogen peroxide, water and sodium hydroxide with the aid of heat to produce compound Vlllp; in step C esterifying one mole of compound Vlllp with about 1.1 to 1.3 moles of methylfulfonyl chloride, in the presence of 1.1 to 1.3 moles of triethylamine in anhydrous benzene to produce compound lXp; in step D cyclizing one mole of compound lXp with about 1.4 to 1.6 moles of sodium hydride in dimethylformamide to produce compound Xp', in step E reducing one mole of compound Xp with about 1.0 to 1.5 moles of lithium aluminum hydride in anhydrous tetrahydrofuran to produce compound Xlp; and in step F cleaving the ether function of Xlp by treatment with about 1.5 to 2.5 moles of boron tribromide to produce compound Xllp.

For the purpose of this disclosure the term inert organic solvent" means an organic solvent that does not participate in the reaction to the extent that it emerges unchanged from the reaction. Such solvents are methylene, chloride, chloroform, dichloroethane, tetrachloromethane, benzene, toluene ether, ethyl acetate, xylene, tetrahydrofuran, dioxane, dimethylacetamide, dimethylformamide. and the like when an acid halide is employed. When an alkylation reaction is being performed, the inert solvent used may also include (lower- )alkanols such as methanol, ethanol, n-propanol, isopropanol and the like. The term organic tertiary amine" means a tertiary amine commonly employed as a proton acceptor in alkylation and acylation reactions. Such amines are tri(lower)alkylamines, e.g., trimethylamine, triethylamine, and the like, pyridine, dimethylaniline, N-methylpiperidine, and the like.

PREPARATION OF THE STARTING MATERIALS CHO XIIIa 4a-( Z-Aminoethyl l ,2,3,4,4a,9-hexahydro-6- methoxyphenanthrene Step A CH O 3 ,4-Dihydro-7-methoxy-2,2-tetramethylenel 2H naphthalenone (Ila) A nitrogen atmosphere was maintained throughout the following reaction. To a stirred and reluxing suspension of 12 g. (0.5 mole) of sodium hydride in 100 ml. of dry benzene was added during 30 minutes, 16.6 g. (0.2 mole) of anhydrous t-amyl alcohol. The reac tion mixture was stirred and refluxed during 15 minutes, and then a solution of 35.2 g. (0.2 mole) of 7- methoxy-3,4-dihydro- 1 2H)-naphthalenone (la) in 100 ml. of dry benzene was added dropwise. After an other 15 minutes, 54.0 g. (0.25 mole) of 1,4- dihromobutane were added over a period of 15 minutes followed by 100 ml. of dry benzene. The resulting reaction mixture was stirred and refluxed during 50 hours. it was then cooled, washed twice with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residual yellow oil was dissolved in 400 ml. of petroleum ether (b.p. 30-60 C. treated with charcoal, filtered and the solvent evaporated. The resulting clear light yellow oil (457 g.) was distilled at reduced pressure and the fraction boiling at 120123 C./0.05 mm. was collected. This procedure yielded 29.4 g. of colorless spiro ketone lla. The infrared (IR) and nuclear magnetic resonance (NMR) spectra were consistent with the structure.

Anal. calcd. for C H O z C, 78.22; H, 7.88.

Found: C, 77.96; H, 7.93.

Step B To a stirred solution of 13.8 ml. (0.022 mole) of 1.6 M n-butyl lithium in hexane at C. under nitrogen was rapidly added 13.8 ml. of anhydrous tetrahydrofuran (THF) followed immediately by a solution of 0.82 g. (0.02 mole) ofacetonitrile in 20 ml. THF which was added during 7 minutes. After stirring for 1 hour at -80 C., the resulting white suspension was treated during 5 minutes with a solution of 4.60 g. (0.02 mole) of the spiroketone 11a in 20 ml. THF. The cold bath was removed and the solution was stirred for 10 minutes before it was poured into ice-water acidified with hydrochloric acid. The layers were separated, and the aqueous layer was extracted with three 25 ml. portions of benzene.

After drying over anhydrous sodium sulfate, evaporation of the solvent and recrystallization of the remaining solid from chloroform, there was obtained 4.4 g. (80% ofwhite solid llla, m.p. l40-l42 C. The IR and NMR spectra were consistent with the structure.

Anal. calcd. for C, H- NO- C, 75.24; H, 7.80; N, 5.16.

Found: C, 75.12: H, 7.91; N, 4.89. Step C CH O l-( Z-Aminoethyl )-7-methoxyl ,2,3,4-tetrahydro-2,2- tetramethylene l -naphthol (IVa) To a stirred suspension of 0.57 g. (0.015 mole) of lithium aluminum hydride in 20 ml. anhydrous tetrahydrofuran (THF) under N was added a solution of 2.7 l g. (0.01 mole) of Illa in 20 ml. tetrahydrofuran. The reaction mixture was stirred for 4 hours at room temperature (r.t.). It was then cooled and treated with 0.6 ml. of water. The inorganic material was filtered off and washed well with ether. The filtrate was extracted with two portions of ml. of IN hydrochloric acid. The extract was basified with aqueous ammonia, and the free base was taken up in ether. After drying over anhydrous sodium sulfate and evaporation of the solvent, there was obtained 2.2 g. of slightly yellow oil IVa. It was converted to the oxalate salt in acetone and recrystallized from methanol. This procedure yielded 2.9 g. (76%) of white solid, containing 1 mole of methanol of crystallization; m.p. l78l80 C.

In another experiment lVa was obtained from Ila without isolation of Illa as follows:

4.6 g. (0.02 mole) of the spiroketone Ila in ml. of tetrahydrofuran was converted to the nitrile IIIa according to the procedure described on the preceding page. To the resulting cold solution (-80 C.) of Illa, was added 1.14 g. (0.03 mole) oflithium aluminum hydride in small portions. After the addition had been completed, the reaction mixture was stirred at r.t. for 4 hours. After work up as above, there was obtained 5.7 g. (75% overall) of the oxalate salt of IVa. m.p.

l79-180 C. In both procedures, the IR and NMR 45 spectra were consistent with the desired product.

I@% l 011 0 E 0x 0 Found: C. 63.41; H, 7.43; N, 3.79. Step D 4a-( 2-Aminoethyl )-l ,2,3,4,4a,9-hedahydro-6- methoxyphenanthrene (Va) Method A Compound lVa l 1.50 g. (000548)] (free base liberated from 2 g. of oxalate salt) in 5 ml. of ether was treated with 1.5 ml. of concentrated HCI under N at 5560 C. for 5 hours. To the cooled mixture were added in succession 10 ml. ofether and 10 ml. of water. After shaking, the two layers were separated. The acidic layer was made alkaline with aqueous ammonia and extracted with ether. The ether layer was dried (K CO=,) and concentrated to yield 1.30 g. of pale yellow oil Va. It was converted to an oxalate salt in ace tone. The crystals were filtered and washed with a small amount of methylene chloride. The IR and NMR spectra were consistent with the structure.

Yield 1.7 g. (96% of white solid. mp. l87-l89 C.

Anal. calcd for C, H. -,NO.C H O C, 65.69; H, 7.25; N, 4.03.

Found: C, 65.46: H, 7.20; N, 3.85.

Method B 120 g. of the oxalate salt of lVa was slurried in 700 ml. of water, and to it was added 400 ml. of benzene and 60 ml. of concentrated ammonia. The mixture was stirred until all the solid had disappeared (ca. 15 minutes) and then the layers were separated. The water layer was extracted with another 100 ml. of benzene, and the combined benzene layers were shaken with 200 ml. of saturated NaCl solution, filtered over K CO and concentrated in vacuo. The residual oil (ca. 90 g.) was dissolved in 300 ml. of ether in a 1 liter round bottom flask and while cooling with an ice-water bath and swirling, to it was added carefully 90 ml. of concentrated HCI and then gently refluxed on the steambath for three hours in a closed system using an oil bubbler. Then the layers were separated, and to the water layer was added 150 ml. of water. After cooling, the solid was filtered off and washed with 50 ml. of acetonitrile to yield 8085 g. of the HCl salt. From the mother liquor a further crop of the product can be obtained by liberating the free base and repeating HCl treatment as above. The product was recrystallized as the hydrochloride from methanol-ether; m.p. 135 C. (dec.).

Anal. calcd. for C H NO.HCI.CH OH: C, 66.34; H, 8.66; N, 4.29.

Found: C, 66.34; H, 8.02; N, 4.46.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Example 1 VI Is.

To a cooled (ice bath) and stirred solution of 25.0 g. of Va and 1 1.0 g. of triethylamine in ml. of CH Cl was added dropwise a solution of 10.5 g. (0. 1 mole) of cyclopropyl carbonyl chloride in 15 ml. CH CL during 15 minutes. The reaction mixture was treated with water and the layers separated The organic layer was dried (Na SO and evaporated to dryness. The residual oil was treated with 30 ml. of ether and after standing for 2 hours at r.t. it crystallized. It was filtered to give 25.56 g. of white solid mp. l2()-125 C. Recrystallization from methanol afforded analytical sample,

mp. l26l30 C., of compound Vlla. The Infrared Anal. calcd. for C ,H ,,NO C, 73.44; H, 8.5l; N, (IR) and Nuclear Magnetic Resonance (NMR) spectra 4.08. were consistent with the structure. Found: C, 73.40; H, 8.59; N, 4.07.

Anal. calcd. for C H NO- C. 77.50; H, 8.36; N,

Example 3 4.30. 5

H H I 6 C150 VIIIa.

Found: C, 77.2]; H, 8.40; N, 4.09. To a solution of 1.94 g. (5.648 m.mole) of Villa and 0.808 g. (8 m.mole) of triethylamine in 30 ml. dry ben- Example 2 zene was added dropwise with cooling (ice bath) a so- H 0 It OH H 0 4 l a' 0250 E 011 0 VIIa VIIIa.

52 ml. of approximately lM boron trihydride/tetlution of 8 ml. (8 m.mole) of a 1M mesyl chloride in rahydrofuran (THF) solution was added to a solution benzene. The reaction mixture was left at r.t. for 3 0f Tl-mole) 0f V113 in y and hours. It was treated with water and the layers sepathe resulting reaction mixture was let standing at r.t. for rated, Th benzene l i was h d i h dil 4 hours- [t was decomposed with 1 2 9 HCl and water. It was dried (Na SO and evaporated 5N NaOH, and 30% 2 2- The reaction mixture to dryness to yield a solid residue. This was treated with was refluxed f 20 m cooled, treated h water ether and filtered to give 2.2 g. of lXa {m.p. l2()-l 22 and acidified with concentrated HCI. The acidic solu- (j A i l le recrystallized from tion was extracted with benzene, and the benzene solu- CH2C|2 ether, |23 124 C, The IR and NMR tion was dried (Na SO and evaporated to dryness to 0 were Consistent i h h t t re,

yield 4.22 g. ofa neutral oil. The acidic solution was ba- A L l u f C H.,,NO,,S; C, 62.68; H, 7.41; N, sified with NH OH, and extracted with CH Cl The 3 32 CH CI solution was dried and evaporated to dryness to F d; C 62,32; H, 739; N, 3. [8.

yield 1.9 g. of basic oil.

The neutral oil contained a mixture of product Villa Example 4 O OMS N v as .H

CH 0 E CH 0 IXa. Xe.

- (isomorphinan) and an unknown side product. 2.2 g. of product Vllla To a cooled (ice salt bath) and stirred suspension of was obtained as a white crystalline solid (mp. 1 17) by 0.126 g. (5.25 m.mole) of NaH in 5 ml. dry DMF was treating the crude oil with ether and allowing it to stand added dropwise a solution L48 g. (3.5 m.mole) of lXa at r.t. to crystallize. The analytical sample of Villa was in 15 m]. dry DMF. The reaction mixture was stirred at recrystallized twice from CH Cl ether. m.p. r.t. for 18 hours. It was decomposed with water and exl3()1 3 1 C. The [R and NMR spectra were consistent tracted with benzene. The benzene extracts were dried with the structure. and evaporated to dryness to give [.2 g. of Xa. Analyti- 19 cal sample was distilled b.p. 165l70/0.0l-0.05. The IR and NMR were consistent with the structure.

Anal. calcd. for C H NO C. 77.50; H, 8.37; N, 4.30.

Found: C. 77.56; H. 8.44; N. 4.1.5.

Example A solution of 46.2 g. (0.22 mole) of trifluoroacetic anhydride in 50 ml. of CH Cl was added dropwise to a cooled (ice-bath) and stirred solution of 51.4 g. (0.2 mole) of Va and 22.22 g. (0.22 mole) of triethylamine in 150 ml. of CH C1 The reaction mixture was decomposed with icewater and the layers separated. The CH Cl solution was washed with dilute HCl, water and then dried (Na SO It was evaporated to dryness to yield a solid residue weight 67.0 g. This was dissolved in ether and diluted with a large amount of petroleum ether. After filtration, there was obtained 58.0 g. of solid Vllb, rn.p. 99101 C. The IR and NMR were consistent with the structure.

Anal. calcd. for C H NO Ee C. 64.58; H, 6.27; N. 3.96.

Found: C, 64.82; H, 6.25; N, 3.82.

20 was heated to an internal temperature of 50 C. for 30 minutes. lt was then cooled. treated with 100 ml. of cold H 0 and acidified carefully with concentrated HCl. The reaction mixture was extracted with benzene. The benzene solution was dried (Na SO and evaporated to give 11.7 g. of a crude product. primarily Vlllb.

H O 1 ll 0 3 CH VIII) 600 mg. of crude Vlllb was chromatographed through a silica gel column 15 g. Elution with a mixture of benzene ether (9:1 yielded 100 mg. of an unidentified by-product (Rf 0.71 silica, benzene:ether, 3:2). Further elution with benzcnezether. (1:1 afforded 430 mg. of the desired product (Rf 0.32 silica, benzene:ethcr, 3:2). The IR and NMR were consistent with the structure.

Anal. calcd. for C H NO F C. 61.44; H, 6.51; N, 3.77.

Found: C. 61.60; H. 6.74; N, 3.63.

The acidic aqueous solution was basified with NH OH and extracted with CH Cl to give 450 mg. of a basic oil whose structure was not investigated.

Example 7 To a cooled (ice-bath) and stirred mixture of l 1.2 g. (30.18 m. mole) of crude Vlllb and 4.51 g. (45 in.

Example 6 mole) of triethylamine in ml. of dry benzene was H O ,OH

H it K JCF l R N-CCF c 3 3 H3 E (II-I 0 To a cooled (ice-hath) and magnetically stirred solution of 10.5 g. (30 m. mole) of Vllb in ml. of dry THF was added dropwise 75 ml. (75 m. mole) of 1 M BH /THF solution. After addition. the reaction mixture was kept in a cold room for 18 hours and then at r.t. for 4 hours. It was treated carefully with 3 ml. H 0. 16 ml. 5N NaOH.-1.4 ml. 30% H 0 and the resulting mixture VIIIb added dropwise a solution of 5.16 g. (45 m. mole) of mesyl chloride in 10 ml. dry benzene. After addition, the reaction mixture was stirred in the cold for 30 minutes and at r.t. for 3 hours. It was then treated with ml. of water. The layers were separated, and the aqueous layer extracted with CH Cl The combined organic extracts were washed with dilute HCl followed by wa- Example 8 The IR (HCl salt) and NMR (free base) spectra were consistent with the structure.

Anal. calc'd. for C H- NOHCI: C. 69.49; H, 8.23; N. 4.77.

Found: C, 69.48; H. 8.38; N. 4.62.

By varying the work up temperature, the ratio of products Xb and Xllla can be adjusted. in another experiment 9.09 g. m.moles) of Xh in 25 ml. dry THF reacted with 0.72 g. m.mole) of NaH in H) ml. dry DMF under the same condition as above. During the work up, the reaction mixture was well cooled with an ice-salt bath and then decomposed with ice water. This To a cooled (ice-bath) and stirred suspension of 0.324 g. (13.5 m.mole) of NaH in 5 ml. dry DMF was added dropwise a solution of 4.05 g. (9 m.mole) of [Xb in 20 ml. dry DMF. The reaction mixture was stirred at r.t. for 6 hours and then it was cooled, decomposed with 10 ml. of water, and extracted with benzene. The benzene solution was dried (Na SO and evaporated to give 3.55 g. of an oil. This was taken up in ether and extracted with dilute HCl. The ether solution was dried and evaporated to give [.25 g. of neutral oil Xb. The acidic solution was basified with NH OH, and extracted with CH Cl The CH Cl solution was dried and evaporated to give L40 g. of basic oil Xllla.

A sample of neutral oil Xb was distilled b.p. l40-l45 C./0.0 1-0.05 mm. The [R and NMR spectra of Xb were consistent with the structure.

XIIa.

Anal. calcd. for C H NO F C, 64.58; H, 6.28; N, 3.96.

Found: C, 64.49; H, 6.34; N, 3.97.

The basic oil 1.4 g. was taken up in dry ether, filtered through celite-charcoal. and converted to its HCl salt in dry ether to give 1.42 g. of HCl salt of Xllla. A sample was recrystallized from methanol-acetone and dried under high vacuum at 80 C., m.p. 293295 C. (d).

XIIIa afforded 5.7 g. of neutral compound Xb and l.] g. of basic compound Xllla.

The basic compound Xllla can be obtained from the amide Xb by treatment with NaOH in aqueous ethanol. Thus 5.4 g. of Xb and 20 ml. of IN sodium hydroxyde in 80% aqueous ethanol was refluxed for 15 minutes. The reaction mixture was cooled, diluted with water and extracted with ether. After drying and evaporation of the ether, there was obtained 4.0 g. of the basic compound Xllla.

A simplified procedure consists in carrying out the above hydrolytic procedure to the mixture of Xb and Xllla thus leading to a single product. namely the secondary amine Xllla.

Example 9 To a cooled (ice-bath) and stirred solution of 5.0 g. (l9.45 m.mole) of Xllla and 2.12 g. (2| m.mole) oftriethylamine in ml. cH cn was added dropwise a solution of 2.49 g. (2! m.mole) of cyclobutylearbonyl chloride in l0 ml. CHzClg. After addition. the reaction mixture was treated with water and the layers separated. The CH Cl layer was washed with dilute HCl and water. It was dried (Na-2504) and evaporated to dryness to give 5.98 g. (90%) of an oil. A sample was distilled b.p. l65l70 C./0.0l-0.05 mm. (Xc). The IR and NMR spectra were consistent with the structure.

Anal. calcd. for C H NO C, 77.84; H, 8.61; N, 4.13.

Found: C. 77.55; H, 8.72; N, 4.01.

Example 10 A solution of 5.67 g. (16.68 g.mole) of Xc in 40 ml. of dry THF was added dropwise to a suspension of l .0 g. lithium aluminum hydride (LAH) in 10 ml. dry THF at r.t. The reaction mixture was refluxed for 4% hours. There was then added, in succession, 1 ml. H 0, 1 ml. N NaOH and 3 ml. H O. The reaction mixture was filtered and the cake washed well with ether. The organic filtrate was extracted with dilute HCl and water The combined acidic solution was basified and extracted with CH Cl The CH CI, solution was dried and evaporated to give 4.55 g. of basic Xlc.

CH O

XIIIa.

A sample was distilled b.p. l60l65 C./0.0l-O.()5 mm. The IR and NMR spectra were consistent with the structure.

Anal. calcd. for C H NO: C, 81.18; H, 9.60; N, 4.30.

Found: C. 81.30; H, 9.67; N, 4.18.

Example 1 l 5 g. (27 m.mole) of BBr in m1. dry 01.0.. After addition, it was stirred at r.t. for 30 minutes. The reaction mixture was decomposed with water, basified with Nl-LOH and the layers separated. The basic layer was extracted with CH Cl and the combined CH C1 solution was dried and evaporated to dryness to give 4.0 g. of Xllc. This was converted to its HCl salt in acetone with 3 ml. concentrated HCl acid to give 4.0 g. of the salt. The salt was recrystallized twice from ethanol to give 2.1 g. of Xllc, m.p. 263265C. (d). as the HCl salt. The IR (HCl salt) and NMR spectra were consistent with the structure.

Anal. calc'd. for C ,H ,,NO.HCl: C, 72.49; H, 8.69; N, 4.03.

Found: C, 72.27; H, 8.79; N, 4.08.

Example 12 Xld.

Example I 3 25 26 Substitution in the procedure of Example II for the B. Substitution in the procedure of Example I] for Xlc used therein of Xld produces the product Xlld, the Xlc used therein of Xlf produces the product Xllf.

Example 14 Example l6 Substitution in the Procedure of Example for A. Substitution in the procedure of Example 10 for the bromide used therein Of methyl bromide PI'O- the compound Xc used therein of ompound X3 produties the product IB- duces the compound Xla.

B. Substitution in the procedure of Example II for the Xlc used therein of Xle produces the product Xlle. 45 B s b i i i th procedure f Example I l f Example l5 CH c=cn--c Br XIIIa.

A. Substitution in the procedure of Example 12 for the mp un Xlc sed therein of comp und Xla prothe allyl bromide used therein of 3,3-dimethylallyl bro- @088 e mpo n XlliL mide produces the product Xlf.

Example [7 XIz A mixture of Xlz (().l mole), 160 ml. of n-octanol and 28.0 g. of KOH pellets is refluxed under nitrogen for 45 minutes. After cooling, the mixture is treated with water and ether (600 ml.) The water layer is discarded, and the organic layer is extracted with 300 ml. of 2N HCl and 2 X 300 ml. of water. The combined aqueous extracts are basified with aqueous ammonia and the free base is taken up in ether, to yield the product Xllla after drying over K CO and evaporation. The product is characterized by conversion to the oxalate salt in anhydrous ether which is recrystallized from an acetone-methanol mixture.

We claim:

l. The process of preparing compounds having the formula I l XIIp in which R is H or CH; and n is an integer of l to 3; which process comprises the consecutive steps of A. acylating one mole of the compound having the formula in which R is (lower)alkyl of l to ID carbon atoms, with at least one mole of an aeylating agent having the formula in which X is OH, Cl, Br or I, R is (lower)alkyl of l to 9 carbon atoms, (CH2)"C H in which R is H or CH,, and n is 0 or an integer of l or 2, in an inert organic solvent selected from the group consisting of methylene chloride, benzene, xylene, ether, diehloroethane and chloroform, in the presence of at least one mole or of a tertiary amine selected from the group consisting of triethylamine, trimethylamine, pyridine, N- methylpiperidine and N-methylpyrrolidine to produce the compound having the formula VIIp in which R and R are as above;

B. treating one mole of compound Vllp with at least one mole of boron trihydride, in an anhydrous organic solvent selected from the group consisting of dry tetrahydrofuran, benzene, dioxane, diethylether, diisopropylether and dibutylether, subsequently with at least one mole each of hydrogen peroxide and water in the presence of an alkali metal hydroxide to produce the compound having the formula VIIIp in which R and R are as above;

C. esterifying one mole of compound Vlllp with at least one mole of a (lower)alkyl of l to 10 carbon atoms, benzene or toluene sulfonyl halide, in which halide is ehloro, bromo or iodo, in the presence of a least one mole of a tertiary amine selected from the group consisting of triethylamine, trimethylamine. pyridine, N-methylpiperidine and N- methylpyrrolidine in an inert organic solvent selected from the group consisting of benzene, xylene, toluene, methylenechloride and dichloroethane to produce the compound having the formula in which R and R are as above and R is (lower)alkyl of l to IO carbon atoms, phenyl or tolyl;

D. cyclizing one mole of compound lXp by treatment with at least one mole of sodium hydride, in an inert organic solvent selected from the group consisting of benzene, dimethylformamide, dimethylacetamide, toluene, xylene, tetrahydrofuran and dioxane, to produce the compound having the formula in which R and R are as above;

E. reducing one mole of compound Xp with an excess of lithium aluminum hydride in an inert organic solvent selected from the group consisting of tetrahydrofuran, dioxane, diethylether, dipropylether and dibutylether with the aid of heat to produce the compound having the formula XIp in which R and R are as above; and

F. cleaving the ether function of compound Xlp by treatment with at least an equimolar quantity of pyridine hydrochloride, boron tribromide or hydrobromic acid.

2. The process of claim 1 wherein in step A the mole of compound V is acylated with about 1 to about [.5 moles of acylating agent, in an organic solvent selected from the group consisting of methylene chloride, benzene, xylene, ether, dichloroethane and chloroform, in the presence of at least one mole of a tertiary amine selected from the group consisting of triethylamine, tri methylamine, pyridine, N-methylpiperidine and N- methylpyrrolidine, to produce compound Vllp; in step B one mole of compound Vllp is treated with about 1.5 to about 4 moles of boron trihydride, in an anhydrous organic solvent selected from the group consisting of dry tetrahydrofuran, benzene, dioxane, diethyl ether, dipropylethyl and dibutyl ether, for about 2 to 24 hours, at'a temperature in the range of about C. to

about 30C., following which the mixture is treated with at least an equimolar quantity each of hydrogen peroxide, water and an alkali metal hydroxide with the aid of heat to produce the compound Vlllp with about L0 to 2.0 moles of a (lower)alkylsulfonyl chloride of l to 10 carbon atoms, in the presence of about 1.0 to 3.0 moles of a tertiary amine selected from the group consisting of triethylamine, trimethylamine, pyridine, N-methylpiperidine and N-methylpyrrolidine, in an organic solvent selected from the group consisting of benzene, xylene, toluene, methylene chloride and dichloroethane, to produce compound lXp; in step D cyclizing one mole of compound lXp by treatment with about L0 to about 2.0 moles of sodium hydride in an organic solvent selected from the group consisting of dimethylformamide, dimethylacetamide, benzene, toluene, xylene, tetrahydrofuran and dioxane at about room temperature for a period of about 5 to about 24 hours, to produce compound Xp; in step E reducing one mole of comcpound Xp with about 1.0 to about 2.0 moles of lithium aluminum hydride in an organic solvent selected from the group consisting of tetrahydrofuran, dioxane, diethylether, dipropylether and dibutylether, with the aid of heat, to produce compound Xlp; and in step F cleaving the ether function of one mole of compound Xlp by treatment with an agent selected from the group consisting of hydrobromic acid, boron tribomide and pyridine hydrochloride to produce compound Xllp.

3. The process of claim 2 wherein in step A one mole of compound V, in which R is methyl, is acylated with about [.0 to about 1.2 moles of acylating agent having the formula i HLX in which X is Cl, Br or I and R is (lower)alkyl of l to 10 carbon atoms, (CH- ,),,C H.=.,

in which R is H or CH,-, and n is 0 or an integer of l or 2, in methylene chloride, or dichloroethanc, in the presence of about I to about 2 moles of triethylamine or pyridine to produce compound Vllp; in step B treating one mole of compound Vllp with about 2 to about 3 moles of boron trihydride in tetrahydrofuran or dioxane, and l to 2 moles each of hydrogen peroxide, water and sodium or potassium hydroxide with the aid of heat to produce compound Vlllp; in step C esterifying one mole of compound Vlllp with about 1.1 to about 1.6 moles of methylsulfonyl chloride, in the presence of about L1 to about 1.6 moles of triethylamine or pyridine in benzene, toluene or xylene to produce compound lXp; in step D cyclizing one mole of compound lXp with about 1.3 to L7 moles of sodium hydride in dimethylformamide or dimethylacetamide to produce compound Xp; in step E reducing one mole of compound Xp with about 1.0 to about 1.5 moles of lithium aluminum hydride in anhydrous tetrahydrofuran or di oxane at about reflux temperatures to produce compound Xlp; and in step F cleaving the ether function of Xlp by treatment with about 1.5 to about 4.0 moles of boron tribromide, hydrobromic acid or pyridine hydrochloride in methylene chloride to produce compound Xllp.

4. The process of claim 2 for the preparation of compound Xllp in which R is wherein in step A one mole of compound V in which R is methyl is acylated with about 1.0 to about 1.2 moles of cyclobutylcarbonyl chloride or cyclopropylcarbonyl chloride in methylene chloride. in the presence of 1.0 to 1.3 moles of triethylamine to produce compound Vllp; in step 8 treating one mole of compound Vllp with about 2 to 3 moles of boron trihydride in tctrahydrofurun, followed by 1.0 to 1.3 moles each of hydrogen peroxide, water and sodium hydroxide with the aid of heat to produce compound Vlllp; in step C esterifying one mole of compound Vlllp with about 1.1 to 1.3 moles of methylsulfonyl chloride, in the presence of 1.1 to 1.3 moles of triethylamine in anhydrous benzene to produce compound lXp; in step D cyclizing one mole of compound lXp with about 1.4 to 1.6 moles of sodium hydride in dimethylformamide to produce compound Xp; in step E reducing one mole of compound xp with about 1.0 to 1.5 moles of lithium aluminum hydride in anhydrous tetrahydrofuran to produce compound X1; and in step F cleaving the ether function of Xlp by treatment with about 1.5 to 4.0 moles of boron tribromide. hydrobromic acid or pyridine hydrochloride in methylene chloride to produce compound Xllp. 

1. THE PROCESS OF PREPARING COMPOUNDS HAVING THE FORMULA
 2. The process of claim 1 wherein in step A the mole of compound V is acylated with about 1 to about 1.5 moles of acylating agent, in an organic solvent selected from the group consisting of methylene chloride, benzene, xylene, ether, dichloroethane and chloroform, in the presence of at least one mole of a tertiary amine selected from the group consisting of triethylamine, trimethylamine, pyridine, N-methylpiperidine and N-methylpyrrolidine, to produce compound VIIp; in step B one mole of compound VIIp is treated with about 1.5 to about 4 moles of boron trihydride, in an anhydrous organic solvent selected from the group consisting of dry tetrahydrofuran, benzene, dioxane, diethyl ether, dipropylethyl and dibutyl ether, for about 2 to 24 hours, at a temperature in the range of about 0*C. to about 30*C., following which the mixture is treated with at least an equimolar quantity each of hydrogen peroxide, water and an alkali metal hydroxide with the aid of heat to produce the compound VIIIp with about 1.0 to 2.0 moles of a (lower)alkylsulfonyl chloride of 1 to 10 carbon atoms, in the presence of about 1.0 to 3.0 moles of a tertiary amine selected from the group consisting of triethylamine, trimethylamine, pyridine, N-methylpiperidine and N-methylpyrrolidine, in an organic solvent selected from the group consisting of benzene, xylene, toluene, methylene chloride and dichloroethane, to produce compound IXp; in step D cyclizing one mole of compound IXp by treatment with about 1.0 to about 2.0 moles of sodium hydride in an organic solvent selected from the group consisting of dimethylformamide, dimethylacetamide, benzene, toluene, xylene, tetrahydrofuran and dioxane at about room temperature for a period of about 5 to about 24 hours, to produce compound Xp; in step E reducing one mole of comcpound Xp with about 1.0 to about 2.0 moles of lithium aluminum hydride in an organic solvent selected from the group consisting of tetrahydrofuran, dioxane, diethylether, dipropylether and dibutylether, with the aid of heat, to produce compound XIp; and in step F cleaving the ether function of one mole of compound XIp by treatment with an agent selected from the group consisting of hydrobromic acid, boron tribomide and pyridine hydrochloride to produce compound XIIp.
 3. The process of claim 2 wherein in step A one mole of compound V, in which R2 is methyl, is acylated with about 1.0 to about 1.2 moles of acylating agent having the formula
 4. The process of claim 2 for the preparation of compound XIIp in which R1 is 